One of the main functions of hair is to protect the body against negative impact from the environment. This is true for animals. In the case of human hair this function has become almost completely obsolete. Human hair is frequently removed from the human body for cosmetic reasons. On the human scalp the hair is desired to be thick. On other parts of the body this is not a case. Very often hair is unwanted on other parts of the body, especially on the legs, under the arms and on the face. Mechanical removal of hair is traumatic to the skin. Thus it is desirable to reduce the velocity of hair growth in order to make mechanical removal less frequently.
Furthermore there are pathological hair growth disorders (e.g. hirsutism, folliculitis, pseudofolliculitis barbea) that require medical treatment.
U.S. Pat. No. 5,753,612 discloses a method for inhibiting hair growth by administration of activin or activin agonists. A mixture containing activin A or derivatives of activin A and its use to suppress hair follicle cell proliferation is disclosed.
WO 01/74317 discloses methods of modulating hair growth. The methods include modulating VEGF (Vascular Epidermal Growth Factor) activity, e.g. modulating VEGF gene expression and/or modulating VEGF protein production and/or activity to modulate hair growth and hair thickness. The method can be used to either promote or inhibit hair growth or hair thickness.
EP-A 0 700 282 discloses a cosmetic process of reducing mammalian hair growth, comprising selecting an area of skin on which reduced hair growth is desired and applying to said area of skin a composition including an inhibitor of 5-lipoxygenase in an amount effective to reduce hair growth.
According to U.S. Pat. No. 6,121,269 mammalian hair growth is reduced by applying to the skin an inhibitor of protein—tyrosine kinase.
According to WO 96/09806 mammalian hair growth is reduced by applying to the skin a composition including an inhibitor of protein kinase C.
According to WO 92/00069 the rate and character of mammalian hair growth is altered by applying topically to the skin a composition containing an inhibitor of the enzyme gamma-glutamyl transpeptidase.
FR-A 2 753 375 discloses that a sulfotransferase inhibitor reduces and prevents the regrowth of hair.
According to U.S. Pat. No. 5,468,476 mammalian hair growth is reduced by applying to the skin an inhibitor of nitric oxide synthetase.
WO 98/02134 discloses the utilization of serine proteases and their ability to induce programmed cell death and apoptosis in the follicular papillae to affect changes in mammalian hair growth.
According to U.S. Pat. No. 6,299,865 mammalian hair growth is reduced by applying to the skin an inhibitor of alkaline phosphatase other than cromoglycate or a salt thereof.
EP-A 0 943 311 discloses a method of inhibiting hair growth, which comprises administering an inhibitor of elastase-like enzymes or a neutral endopeptidase inhibitor. EP-A 0 943 311 also discloses the use of an inhibitor of elastase-like enzymes or of a neutral endopeptidase inhibitor for the preparation of a hair-growth inhibitor.
According to WO 99/62465 hair growth is reduced by inhibiting the activity of a matrix metalloproteinase in the skin.
EP-A 0 754 024 discloses the application to the skin area of a composition of an ornithine amino transferase inhibitor in a quantity efficient to reduce hair regrowth.
EP-A 1 074 240 discloses a method for reducing hair growth, hair follicle and hair shaft size and hair pigmentation. It comprises the use of one or more substances obtained from the botanical family leguminosae, solanacae, graminacae and curcubitacae. The substances contain one or more serine protease inhibiting compounds and antiandrogenic isoflavones.
EP-A 0 750 489 discloses the inhibition of hair growth by applying an inhibitor of a cysteine pathway enzyme.
EP-A 0 700 288 discloses a cosmetic process of inhibiting mammalian hair growth, comprising the application to the skin of a composition including an inhibitor of cyclooxygenase.
U.S. Pat. No. 6,248,751 discloses a process for inhibiting mammalian hair growth comprising the application of a composition containing a cyclooxygenase inhibitor.
WO 200050002 (U.S. Pat. No. 6,121,269) discloses a method of reducing hair growth comprising the application of a composition comprising a protein-tyrosine kinase inhibitor.
WO 01/72266 discloses cosmetic compositions having retarding action on the regrowth of superfluous hair. These compositions contain fatty acids and antiandrogenic sterols from serenoa (Serenoa repens) and/or from Cucurbita seeds (Cucurbita pepo).
EP-A 0 711 541 discloses a composition (e.g. a solution) for inhibiting hair growth in mammals which contains as active ingredient a compound which blocks glucose transfer across the membranes of the cells of hair follicles. According to EP-A 0 711 541 a preferred embodiment is the use of phloretin as a glucose blocking compound. Other embodiments are the use of steviol, cytochlasin B, 3,3′ diallylstilbesterol and 3,3′-di-(2-chlorallyl)-stilbesterol.
WO 96/26712 discloses a method of inhibiting hair growth that includes applying a dermatologically acceptable composition containing a non-steroidal suppressor of angiogenesis.
According to U.S. Pat. No. 5,674,477 mammalian hair growth is reduced by applying to the skin a dermatologically acceptable composition including a catechin compound.
According to U.S. Pat. No. 6,235,737 mammalian hair growth is reduced by applying to the skin a composition that increases cellular ceramide levels.
U.S. Pat. No. 6,379,673 discloses an herbal formulation for therapeutic and cosmetic applications for the treatment of general skin disorders that contains an aqueous extract of Gymnena sylvestre. 
JP-A 2001 226 274 discloses a lipase inhibitor that comprises a crude drug or its extract such as guava leaf (Psidium guajava), hop (Humulus lupulus), Apocynum venetum leaf, Gymnema leaf (Gymnema sylvestre), and/or Gardenia fructus (Gardenia jasminoides var. grandiflora). The lipase inhibitor according to JP-A 2001 226 274 has the following functions: anorectic, antidiabetic, antilipemic and hypotensive.
WO 01/17486 discloses a method for the cosmetic treatment of skin impairments and baldness by applying deanol or derivatives thereof (deanol is dimethylaminoethanol).
JP-A 2292208 discloses a cosmetic preparation that contains substances obtained from leaves of Gymnema sylvestre, Zizyphus jujuba, bark and peelings of Malus pumila and further substances.
JP-A 02292208 discloses a cosmetic preparation that contains substances obtained from leaves of Gymnema sylvestre. The substances are obtained by extraction. The solvent used for extraction is water, alcohol, or mixtures of water and alcohol. The cosmetic preparation according to JP-A 02292208 can be used for the treatment of blotches and freckles.
JP-A 01258623 discloses a composition that stimulates hair growth and blood circulation and prevents baldness. It contains chitin and chitosan in combination with hydrolysing enzymes, organic acids, and substances of Gymnema sylvestre and Isagol (hemicellulose of Plantag).
Gymnema sylvestre (Retz.) R. Br. ex Schult (belonging to the family Asclepiadaceae) is a woody climbing plant that grows in the tropical forests of central and southern India. The leaves are used in herbal medicine preparations. It is an Ayurvedic herb, it used to be known as “destroyer of sugar”, because in ancient times Ayurvedic physicians observed that chewing a few leaves of Gymnema sylvestre suppressed the taste of sugar. Today it is used all over India for controlling blood sugar (Baskaran K., Kizar Ahamath B., Radha Shanmugasundaram K., Shanmugasundaram E. R., Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin-dependent diabetes mellitus patients, J Ethnopharmacol, volume 30, pages 295 to 300, 1990).
The plant Gymnema sylvestre contains two resins (one of them is soluble in alcohol), gymnemic acids, saponins, stigmasterol, quercetol, and the amino acid derivatives betaine, choline and trimethylamine.
Gymnema sylvestre is stomachic, diuretic, refrigerant, astringent, and tonic. It has been found to increase urine output and reduce hyperglycemia in both animal and human studies.
Gymnema sylvestre has been used in India for the treatment of diabetes for over 2,000 years. The primary application was for adult-onset diabetes, a condition for which it continues to be recommended in India today. The leaves of the plant Gymnema sylvestre were also used for stomach ailments, constipation, water retention and liver disease (Baskaran K., Kizar Ahamath B., Radha Shanmugasundaram K., Shanmugasundaram E. R., Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin-dependent diabetes mellitus patients, J Ethnopharmacol, volume 30, pages 295 to 300, 1990).
The extract of the plant Gymnema sylvestre contains gymnemic acids, flavonoids and phenolic acids. Phenolic acids are acids that have a hydroxybenzene moiety in their structure, e.g. p-hydroxybenzoic acid, protocatechuic acid, vanillic acid, gallic acid, caffeic acid, p-coumaric acid, ferulic acid.
The inhibiting activity of phosphodiesterase (in bovine taste papillae) (and consequently an increase in cAMP) for gymnemic acids is known (Kurihara K., Inhibition of cyclic 3′5′-nucleotide phosphodiesterase in bovine taste papillae by bitter taste stimuli, FEBS Letters, volume 27, pages 279 to 281, 1972). The enzyme phosphodiesterase increases the content of cAMP and there is a hypothesis that hair growth inhibition may be regulated through this pathway (see also: Hoffmann R. et. al., Interleukin-1β-induced inhibition of hair growth in vitro is mediated by cyclic AMP, J. Invest. Dermatol., volume 108, pages 40 to 42, 1997).
The factors that influence the growth of hair follicles are not completely known. It is known that numerous growth factors (cytokines, receptors and hormones) are critical for their development (Rusting R. L., Scientific American, volume 284, pages 55 to 63, 2001 and Sawaya, Curr. Probl. Dermatol., volume 13, pages 206 to 210, 2001).
The mechanisms of hair growth have been studied intensively. The regulation of the hair cycle, the problem of baldness and the search for molecules capable to control hair growth are of interest for pharmaceutical and for cosmetic reasons.
The “hair cycle” is the growth of hair in three phases, which are the growing of hair (anagen phase), the weakening of hair (catagen phase) and the falling out of hair (telogen phase). Baldness may be due to the dysfunction of the hair cycle in a way that comprises a shortened anagen phase and a too early entry in the catagen phase, whereby promoters influence this entry in the catagen phase.
Interleukin 1 (IL-1) can inhibit the growth of hair follicles in vitro (Harmon C. S., Nevis T. D., Lymphokine, Cytokine Res., volume 12, pages 197 to 203, 1993).
Transgenic mice that over-express IL-1α in basal keratinocytes show patchy hair loss (Groves R. W. et al., Analysis of epidermal IL-1 family members in vivo using transgenic mouse models, J. Invest. Dermatol., volume 102, page 556, 1994).
IL-1β was found to be expressed aberrantly in active alopecia areata, when the treatment of baldness is based on antagonists of IL-1β mediated intrafollicular pathways leading to the weakening of hair follicles and finally to the loss of hair (Hoffmann R., Happle R., Does Interleukin-1 induce hair loss in vivo? Dermatology, volume 191, pages 273 to 275, 1995).
The signaling pathways of IL-1β induced suppression of hair growth are unknown. Some pharmacological data suggest that IL-1β induced hair growth inhibition is mediated by cAMP (cAMP or cyclic AMP is cyclic adenosine monophosphate) (Hoffmann R. et al, Interleukin-1β-induced inhibition of hair growth in vitro is mediated by cyclic AMP. J. Invest. Dermatol., volume 108, pages 40 to 42, 1997 and Shirakawa F. et al, Cyclic AMP—an intracellular second messenger for interleukin-1, Proc. Natl. Acad. Sci. USA, volume 85, pages 8201 to 8205, 1988).
II-1 utilizes different signaling pathways, one of them is the cAMP-activated protein kinase pathway.
The role of cAMP in hair follicle cells is not known. It has been assumed that it inhibits the differentiation of matrix cells and that it inhibits cellular proliferation.
The problem underlying the present invention is the need for further substances that can be used to suppress, retard or inhibit hair growth either for medical or for cosmetic reasons.